CLIPPERS Syndrome - Journal of the Belgian Society of Radiology

Transcription

Maenhoudt, W et al 2016 A Rare Cause of Dizziness and Gait Ataxia:
CLIPPERS Syndrome. Journal of the Belgian Society of Radiology, 100(1): 20,
pp. 1–4, DOI: http://dx.doi.org/10.5334/jbr-btr.997
CASE REPORT
A Rare Cause of Dizziness and Gait Ataxia:
CLIPPERS Syndrome
Wim Maenhoudt*, K. Ramboer* and V. Maqueda†
In this paper we report the case of a 52-year-old woman with multiple contrast enhancing lesions associated with a chronic lymphocytic inflammation of the infratentorial structures. We discuss the symptoms,
imaging and treatment of this rare disorder, in which magnetic resonance imaging (MRI) has a crucial role
in the diagnosis. Early recognition on MRI and radiological follow-up are also important to optimize the
treatment.
Keywords: brain; pons; white matter; clippers; steroids
Case report
A 52-year-old patient consults the neurologist with complaints of sustained dizziness, vertigo and unstable gait for
more than a month. She has no relevant medical or family
history. Clinical neurological examination is normal except
for an unstable broad based gait. On electroencephalogram
and standard blood examination there were no significant abnormalities. A brain magnetic resonance imaging
(MRI) showed multiple areas of minimal fluid attenuation
inversion recovery (FLAIR), hyperintense signal and with
punctate as well as curvilinear contrast enhancement
(Figure 1). These lesions were predominant in the cerebellar vermis and hemispheres. In the prerolandic white matter of both cerebral hemispheres there are similar, yet less
pronounced lesions compared to the infratentorial ones
(Figure 2). When compared to an older MR preformed nine
years ago, these lesions were completely new so a congenital vascular malformation could be excluded. Additionally,
more extensive blood tests (paraneoplastic antibodies,
rheumatic factors, serologic test for Borrelia, Syphilis and
HIV) were ordered as well as an electromyography which
all turned out to be negative. Lumbar puncture showed
mild lymphocytosis and mildly elevated protein. Cultures
of CSF, blood and urine were all negative. A CAT scan of
the thorax and abdomen did not show any underlying
malignancy. MR of the cervical spine and PET scan were
also normal. To exclude the possibility of an intravascular
lymphoma, an open biopsy was performed with resection
of the most superficial lesion in the cerebellar hemisphere.
Biopsy results showed a combined polyclonal B- and T-cell
lymphocytes infiltration of the white matter with a largely
*AZ sint lucas, BE
wim.maenhoudt@gmail.com, Kristof.Ramboer@stlucas.be
Department of neurology, AZ Sint Lucas Brugge, BE
Vicky.Maqueda@stlucas.be
†
Corresponding author: Wim Maenhoudt
perivascular distribution which excluded the possibility
of a lymphoma. The diagnosis of “Chronic lymphocytyc
inflammation with pontine perivascular enhancement
responsive to steroids syndrome” (CLIPPERS) was suggested
and the patient underwent a treatment with steroids starting with Solumedrol (1g) during five days followed by several months of Prednisone in maintenance dose combined
with methotrexate. After three months there was a clinical response to glucocorticosteroids as well as radiological improvement on control MRI. This parallel clinical and
radiological evolution, depending on the corticotherapy,
confirmed the diagnosis of CLIPPERS. Almost one and a
half years later, our patient reported a new episode of pronounced dizziness combined with horizontal nystagmus.
A control MRI at that time showed small foci of contrast
enhancement in the pons and the cerebral peduncles
(Figure 3). The patient was treated with five days of Solumedrol IV (1000mg) followed by a higher maintenance
dose. In the following months there was again a good clinical and radiological evolution.
Discussion
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS
syndrome) is a chronic inflammatory disorder of the
central nervous system of unknown etiology which was
first described in 2010 by Pittock et al. as distinct form of
brainstem encephalitis with a predilection for the hindbrain [1]. This condition features brainstem and cerebellar
related symptoms combined with a characteristic pattern
of gadolinium enhancement on MRI.
Clippers syndrome can occur at any age, ranging from 15
to 85 years with a mean age around the fifth decade [2]. It
affects both genders with possibly a minor male predominance. This condition is accompanied by a wide range of
symptoms although almost every known patient reports
complaints of unstable gait, dysarthria and diplopia in a
subacute manner evolving over several weeks. Without
Art. 20, page 2 of 4
Maenhoudt et al: A Rare Cause of Dizziness and Gait Ataxia
Figure 1: Axial FLAIR image (A): multiple punctate and linear FLAIR hyperintense blurry lesions without mass effect (A)
predominatly located in the cerebellar vermis and hemispheres, which become more apperent on contrast-enhanced
T1-weighted image (B).
treatment the natural course of the disease seems to be
relapsing-remitting [2]. Other possible symptoms include
dizziness, nausea, tinnitus, tremor, nystagmus, paraparesis, sensory loss and spasticity. Systemic symptoms (fever,
weight loss) and symptoms related to connective tissue
diseases or rheumaticatic disorders (e.g. arthritis and
uveitis) are generally not a feature of this condition and
the presence of these symptoms should lead to increased
alertness for other causes. Recently the presence of cognitive impairment has been described as a possible long
term finding related to CLIPPERS [3].
A crucial role in the diagnosis of CLIPPERS syndrome is
preserved for MRI imaging of the brain and spinal cord
because it shows a characteristic pattern of punctate and
curvilinear enhancement predominantly but not exclusively at the pons and brachium pontis possibly extending in the medulla and midbrain with or without spread
in the cerebellar white matter in variable degrees. These
individual lesions are very small but may coalesce to form
larger lesions [4]. Additionally, lesions may also occur in
the cervicothoracal spine cord and supratentorial structures such as the cerebral white matter and the deep cerebral nuclei. On FLAIR images these lesions appear blurry
and become more apparent after using contrast. The
small hyperintense areas on FLAIR and T2 images do not
extend beyond the boundaries of the contrast enhancement which means that the lesions do not cause vasogenic oedema [3]. Normally there is no mass effect but
a mild form of swelling of the middle cerebellar peduncle and the pons during relapse has been described [2].
Furthermore the size as well as the number and enhancement of lesions typically decrease with the distance from
Figure 2: Axial T1 with contrast showing multiple discrete curvilinear lesions in the cerebral white matter of
the superior frontal and prerolandic gyrus in both hemispheres.
the pons. Diffusion weighted imaging shows no areas of
restricted diffusion and cerebral angiography is normal.
PET-CT of the brain normally shows no change or minor
hypermetabolism of contrast enhancing areas, considerably less than seen in lymphoma [3]. Although there are
only few long term results, patients with CLIPPERS seems
Figure 3: Coronal (A) and axial (B) contrast-enhanced T1 MRI images after 1.5 years showing new punctate and curvilinear lesions predomanintly in the pons and the right middle cerebellar peduncle (yellow arrows).
to develop significant cerebellar atrophy on follow up MRI
even if there is improvement of the inflammatory process
and resolution of the contrast enhancement [3].
Next to MR imaging, CAT scan of abdomen and chest,
PET-scan, extensive laboratory testing and CSF analysis
are necessary for diagnosis, mainly to exclude the possibility of other alternative causes because the list of differential diagnosis is long; especially primary CNS angiitis
or lymphoma must be excluded. Other rare conditions
which could present themselves in a similar way include
neurosarcoidosis, paraneoplastic disease, infectious process (tuberculosis, neurosyphilis, Whipple’s disease, and
parasitic infection), glioma, Behcet, Bickerstaff brainstem
encephalitis and demyelinating diseases. Some patients
initially diagnosed with CLIPPERS syndrome because of
the typical clinical and radiological pattern later turned
out to be an atypical manifestation of a primary central
nervous system lymphoma [2, 3].
CSF analysis usually reveals an inconsistent pattern
including mild pleocytosis, mild protein elevation and/
or oligoclonal bands which, when serially assessed was
often observed as a transient phenomenon [2]. If other
alternative pathologies cannot be excluded or MR doesn’t
show the characteristic pattern, an additional brain
biopsy should be performed. The results usually show
a perivascular T-cell infiltration, with a predominance of
CD4 cells, in the white matter. Although the underlying
pathogenesis of this condition is poorly understood and
the neuropathological findings are far from specific, these
pathology results suggest an inflammatory disorder with
a vascular or perivascular tropism predominantly located
in the pons and the peripontine region. Some authors
suggest that this immune reaction is possibly related to
a primary venous inflammatory disorder considering
the anatomical arrangement of small intra-axial veins in
the brainstem [2]. Nevertheless this theory is based on
assumptions and further studies are necessary for better
understanding the correlation between the immunological, clinical and radiologic features.
Certainly one of the most important criteria for the
diagnosis of this disorder is the clinical as well as radiologic responsiveness to glucocorticosteroid (GCS) based
immunosuppression [1, 2, 3]. Typically the enhancement of the lesions decreases as a result of the therapy.
Withdrawal of corticosteroid treatment leads to an
exacerbation of symptoms in almost all patients, so
maintenance therapy with chronic glucocorticosteroids is required and is the current standard therapy for
this condition. The actual treatment of choice is a short
course of high-dose IV methylprednisolone followed by
oral GCS in combination with an GCS-sparing immunosuppressant. The GCS-sparing agents are used to reduce
the daily GCS dose and the chance of GCS side effects. If
there is no adequate clinical and radiological response
to glucocorticosteroid therapy within the first months,
the diagnosis of CLIPPERS should be questioned [2].
Since CLIPPERS has only recently been described as a
new disorder, it’s unclear how long maintenance therapy
should be continued. Because it has a similar pathologic
characteristics as vasculitides, is seems favorable to continue the therapy for at least 2–5 years [4].
Conclusion
Clippers syndrome is a rare disorder and has only recently
been described as a new disease entity in 2010 [1]. Current
literature only reports a few cases which raise the question of whether this really is a truly new disease or if it has
simply been misdiagnosed for several years as an atypical
presentation of known clinically and radiologically similar
conditions such as MS, neurosarcoidosis, CNS lymphoma
or CNS vasculitis. The disease seems to be centered at
the pontine region and the brachium pontis with variable involvement of the adjacent structures. The patients
diagnosed with CLIPPERS typically present themselves

with a characteristic pattern of brainstem and cerebellar related symptoms. Diagnosis is based on a combination of clinical, radiological and laboratory investigations
and, if other conditions such as CNS lymphoma remain
a possibility, additional brain biopsy. Another important
criterion is the clinical and radiological response to glucocorticosteroids. Therefore glucocorticosteroids in combination with a GCS-sparing agent is the standard therapy. A
maintenance therapy combined with a GCS-sparing agent
is required to prevent a recurrence of symptoms.
Competing Interests
The authors declare that they have no competing interests.
References
1.
Pittock, S, Debruyne, J, Krecke, KN, et al. Chronic
lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 2010; 133: 2626–2634. DOI: http://
dx.doi.org/10.1093/brain/awq164
2.
Dudesek, A, Rimmele, F, Tesar, S, et al. CLIPPERS:
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perivascular enhancement responsive to steroids.
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385–396. DOI: http://dx.doi.org/10.1111/cei.12204
3.
Simon, N, Parratt, JD, Barnett, MH, et al. Expanding the clinical, radiological and neuropathological
phenotype of chronic lymphocytic inflammation
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Wijntjes, J, Wouda, EJ, Siegert, C, Karas, GB
and Vlaar, AM. Need for prolonged immunosupressive therapy in CLIPPERS – a case report.
BMC Neurology. 2013; 13: 49. DOI: http://dx.doi.
org/10.1186/1471-2377-13-49
How to cite this article: Maenhoudt, W, Ramboer, K and Maqueda, V 2016 A Rare Cause of Dizziness and Gait Ataxia: CLIPPERS
Syndrome. Journal of the Belgian Society of Radiology, 100(1): 20, pp. 1–4, DOI: http://dx.doi.org/10.5334/jbr-btr.997
Published: 05 February 2016
Copyright: © 2016 The Author(s). This is an open-access article distributed under the terms of the Creative Commons
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